This study explored the effects of cucurbitacin E （CUE）, a bioactive compound from Cucurbitaceae, on the metabolism/ pharmacokinetic of tolbutamide, a model CYP2C9/11 probe substrate, and hepatic CYP2C11 expression ...This study explored the effects of cucurbitacin E （CUE）, a bioactive compound from Cucurbitaceae, on the metabolism/ pharmacokinetic of tolbutamide, a model CYP2C9/11 probe substrate, and hepatic CYP2C11 expression in rats. Liquid chro- matography-（tandem） mass spectrometry （LC-MS/MS） assay was used to detect tolbutamide as well as 4-hydroxytolbutamide, and then successfully applied to the pharmacokinetic study of tolbutamide in rats. The effect of CuE on CYP2C11 expression was determined by western blot. CuE （1.25-100μmol· L-1） competitively inhibited tolbutamide 4-hydroxylation （CYP2C11） activity only in concentration-dependent manner with a Ki value of 55.5 μmol L-1 in vitro. In whole animal studies, no signifi- cant difference in metabolism/pharmacokinetic of tolbutamide was found for the single pretreatment groups. In contrast, mul- tiple pretreatments of CuE （200 μg kg-1 d-1, 3 d, i.p.） significantly decreased tolbutamide clearance （CL） by 25% and pro- longed plasma half-time （T1/2） by 37%. Moreover, CuE treatment （50-200 pg kg-l d-1, i.p.） for 3 d did not affect CYP2C11 expression. These findings demonstrated that CuE competitively inhibited the metabolism of CYP2C11 substrates but had no effect on rat CYP2C11 expression. This study may provide a useful reference for the reasonable and safe use of herbal or nat- ural products containing CuE to avoid unnecessary drug-drug interactions.展开更多
基金supported by the National Natural Science Foundation of China (81301908)the Science and Technology Commission of Shanghai Municipality (13ZR1412600, 14DZ2270100)
文摘This study explored the effects of cucurbitacin E （CUE）, a bioactive compound from Cucurbitaceae, on the metabolism/ pharmacokinetic of tolbutamide, a model CYP2C9/11 probe substrate, and hepatic CYP2C11 expression in rats. Liquid chro- matography-（tandem） mass spectrometry （LC-MS/MS） assay was used to detect tolbutamide as well as 4-hydroxytolbutamide, and then successfully applied to the pharmacokinetic study of tolbutamide in rats. The effect of CuE on CYP2C11 expression was determined by western blot. CuE （1.25-100μmol· L-1） competitively inhibited tolbutamide 4-hydroxylation （CYP2C11） activity only in concentration-dependent manner with a Ki value of 55.5 μmol L-1 in vitro. In whole animal studies, no signifi- cant difference in metabolism/pharmacokinetic of tolbutamide was found for the single pretreatment groups. In contrast, mul- tiple pretreatments of CuE （200 μg kg-1 d-1, 3 d, i.p.） significantly decreased tolbutamide clearance （CL） by 25% and pro- longed plasma half-time （T1/2） by 37%. Moreover, CuE treatment （50-200 pg kg-l d-1, i.p.） for 3 d did not affect CYP2C11 expression. These findings demonstrated that CuE competitively inhibited the metabolism of CYP2C11 substrates but had no effect on rat CYP2C11 expression. This study may provide a useful reference for the reasonable and safe use of herbal or nat- ural products containing CuE to avoid unnecessary drug-drug interactions.
